We propose to continue the long term follow up of the Healthy Women Study that began in 1983-84 as the first study of the determinants of risk factors changes among women during the peri- to postmenopause. The HWS originally sampled 541 premenopausal women in 1983-84. This study has pioneered the use of new technologies for evaluating subclinical cardiovascular disease (CVD);first, carotid intimal medial thickness (IMT) in 1994 and then the addition of coronary and aortic calcium measurements using electron beam tomography (EBT) in 1997-98 (n=363). The subclinical vascular disease measurements were repeated twice, 3 years apart (2002-3 and 2004-7). At the 1st EBT study, the women had a mean age of 62;57% of the women had 0 coronary artery calcium (CAC) and by the 3rd EBT 37% of the women with 0 CAC had developed new CAC, an estimated 6% per year. We determined that premenopausal risk factors were the primary determinant of CAC. The extent of peripheral atherosclerosis, aorta and carotid measured at the time of the 1st EBT was an important determinant of the risk of developing new CAC among women with 0 CAC score at the 1st EBT by time of 3rd EBT examination 6 years later. In this application, we plan to repeat the coronary and aortic calcium studies and carotid ultrasound and vascular stiffness. We propose to add maximal exercise testing to determine functional capacity, and to measure cognitive function, history of clinical depression, physical functioning, and sleep quality and duration. We hypothesize that a small number of women, estimated to be 25% (N=75), will continue to have 0 CAC scores at age 73, that premenopausal risk factors will remain the primary determinants of CAC, even to the age of 73. We hypothesize that (a) measures of subclinical disease in other vascular beds, i.e. carotid and aorta, will be a primary determinant of the conversion from no CAC at 1st EBT to subsequent CAC over the 4 EBT measurements;(b) pulse wave velocity will be a predictor of the development of new CAC;and (c) women who have 0 CAC will have better functional capacity, cognitive function, and better sleep, and less depression and functional loss than those who have higher CAC scores, even in the absence of clinical coronary heart disease. We suggest that risk of vascular disease and healthy aging among postmenopausal women is primarily determined by premenopausal lifestyles and risk factors. PUBLIC HEALTH RELEVANCE: In the next phase of the Pittsburgh Healthy Women Study, we propose to test the hypotheses that (a) premenopausal cardiovascular risk factors are strong predictors of progression of coronary and aortic calcification and carotid intima media thickness measured 25 years later;and (b) postmenopausal women with no or low levels of subclinical atherosclerosis have concurrently better functional capacity, cognitive function, and sleep, and less depression and disability than those with higher levels.